全文获取类型
收费全文 | 771篇 |
免费 | 59篇 |
专业分类
830篇 |
出版年
2022年 | 6篇 |
2021年 | 8篇 |
2020年 | 9篇 |
2019年 | 8篇 |
2018年 | 10篇 |
2017年 | 20篇 |
2016年 | 9篇 |
2015年 | 32篇 |
2014年 | 27篇 |
2013年 | 42篇 |
2012年 | 51篇 |
2011年 | 58篇 |
2010年 | 35篇 |
2009年 | 40篇 |
2008年 | 50篇 |
2007年 | 49篇 |
2006年 | 47篇 |
2005年 | 41篇 |
2004年 | 37篇 |
2003年 | 34篇 |
2002年 | 24篇 |
2001年 | 9篇 |
2000年 | 9篇 |
1999年 | 8篇 |
1998年 | 10篇 |
1997年 | 6篇 |
1996年 | 12篇 |
1995年 | 6篇 |
1994年 | 5篇 |
1993年 | 18篇 |
1992年 | 4篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 7篇 |
1988年 | 8篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 4篇 |
1982年 | 5篇 |
1979年 | 3篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1975年 | 4篇 |
1971年 | 4篇 |
1969年 | 3篇 |
1968年 | 2篇 |
1967年 | 5篇 |
1963年 | 2篇 |
1959年 | 2篇 |
排序方式: 共有830条查询结果,搜索用时 15 毫秒
81.
Profile of resistance of human immunodeficiency virus to mannose-specific plant lectins 总被引:6,自引:0,他引:6 下载免费PDF全文
Balzarini J Van Laethem K Hatse S Vermeire K De Clercq E Peumans W Van Damme E Vandamme AM Bölmstedt A Schols D Böhlmstedt A 《Journal of virology》2004,78(19):10617-10627
The mannose-specific plant lectins from the Amaryllidaceae family (e.g., Hippeastrum sp. hybrid and Galanthus nivalis) inhibit human immunodeficiency virus (HIV) infection of human lymphocytic cells in the higher nanogram per milliliter range and suppress syncytium formation between persistently HIV type 1 (HIV-1)-infected cells and uninfected CD4(+) T cells. These lectins inhibit virus entry. When exposed to escalating concentrations of G. nivalis and Hippeastrum sp. hybrid agglutinin, a variety of HIV-1(III(B)) strains were isolated after 20 to 40 subcultivations which showed a decreased sensitivity to the plant lectins. Several amino acid changes in the envelope glycoprotein gp120, but not in gp41, of the mutant virus isolates were observed. The vast majority of the amino acid changes occurred at the N glycosylation sites and at the S or T residues that are part of the N glycosylation motif. The degree of resistance to the plant lectins was invariably correlated with an increasing number of mutated glycosylation sites in gp120. The nature of these mutations was entirely different from that of mutations that are known to appear in HIV-1 gp120 under the pressure of other viral entry inhibitors such as dextran sulfate, bicyclams (i.e., AMD3100), and chicoric acid, which also explains the lack of cross-resistance of plant lectin-resistant viruses to any other HIV inhibitor including T-20 and the blue-green algae (cyanobacteria)-derived mannose-specific cyanovirin. The plant lectins represent a well-defined class of anti-HIV (microbicidal) drugs with a novel HIV drug resistance profile different from those of other existing anti-HIV drugs. 相似文献
82.
83.
Marijke De Saint-Hubert Felix M. Mottaghy Kathleen Vunckx Johan Nuyts Humphrey Fonge Kristof Prinsen Sigrid Stroobants Luc Mortelmans Niko Deckers Leo Hofstra Chris P.M. Reutelingsperger Alfons Verbruggen Dirk Rattat 《Bioorganic & medicinal chemistry》2010,18(3):1356-1363
In this study ‘second generation’ AnxV was specifically labeled with 99mTc in three different ways outside the binding region of the protein to obtain an improved target-to-background activity ratio. The compounds were tested in vitro and in vivo in normal mice and in a model of hepatic apoptosis (anti-Fas mAb). The apoptosis binding was most prominent for the HIS-tagged ‘second generation’ AnxV labeled with 99mTc(CO)3 in comparison to 99mTc-HYNIC-cys-AnxV and 99mTc(CO)3-DTPA-cys-AnxV. 相似文献
84.
Christa Gaskill Jennifer Forbes-Stovall Bruce Kessler Mike Young Claire A. Rinehart Sigrid Jacobshagen 《Plant Physiology and Biochemistry》2010,48(4):239-246
Automated monitoring of circadian rhythms is an efficient way of gaining insight into oscillation parameters like period and phase for the underlying pacemaker of the circadian clock. Measurement of the circadian rhythm of phototaxis (swimming towards light) exhibited by the green alga Chlamydomonas reinhardtii has been automated by directing a narrow and dim light beam through a culture at regular intervals and determining the decrease in light transmittance due to the accumulation of cells in the beam. In this study, the monitoring process was optimized by constructing a new computer-controlled measuring machine that limits the test beam to wavelengths reported to be specific for phototaxis and by choosing an algal strain, which does not need background illumination between test light cycles for proper expression of the rhythm. As a result, period and phase of the rhythm are now unaffected by the time a culture is placed into the machine. Analysis of the rhythm data was also optimized through a new algorithm, whose robustness was demonstrated using virtual rhythms with various noises. The algorithm differs in particular from other reported algorithms by maximizing the fit of the data to a sinusoidal curve that dampens exponentially. The algorithm was also used to confirm the reproducibility of rhythm monitoring by the machine. Machine and algorithm can now be used for a multitude of circadian clock studies that require unambiguous period and phase determinations such as light pulse experiments to identify the photoreceptor(s) that reset the circadian clock in C. reinhardtii. 相似文献
85.
Sigrid B. Thoresen Nina Marie Pedersen Knut Liestøl 《Experimental cell research》2010,316(20):3368-3378
The mammalian class III phosphatidylinositol 3-kinase (PI3K-III) complex regulates fundamental cellular functions, including growth factor receptor degradation, cytokinesis and autophagy. Recent studies suggest the existence of distinct PI3K-III sub-complexes that can potentially confer functional specificity. While a substantial body of work has focused on the roles of individual PI3K-III subunits in autophagy, functional studies on their contribution to endocytic receptor downregulation and cytokinesis are limited. We therefore sought to elucidate the specific nature of the PI3K-III complexes involved in these two processes. High-content microscopy-based assays combined with siRNA-mediated depletion of individual subunits indicated that a specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis, whereas ATG14L, a PI3K-III subunit involved in autophagy, is not required. The unanticipated role of UVRAG and BIF-1 in cytokinesis was supported by a strong localisation of these proteins to the midbody. Importantly, while the tumour suppressive functions of Beclin 1, UVRAG and BIF-1 have previously been ascribed to their roles in autophagy, these results open the possibility that they may also contribute to tumour suppression via downregulation of mitogenic signalling by growth factor receptors or preclusion of aneuploidy by ensuring faithful completion of cell division. 相似文献
86.
Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris 总被引:3,自引:0,他引:3
Diluvio L Vollmer S Besgen P Ellwart JW Chimenti S Prinz JC 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(11):7104-7111
Tonsillar infection with Streptococcus pyogenes may induce several nonsuppurative autoimmune sequelae. The precise pathogenetic mechanisms behind this clinically well-established association are still unresolved. Using TCR analysis, we sought to identify a link between streptococcal tonsillitis and the T cell-mediated autoimmune response in psoriasis. Three patients with streptococcal-induced psoriasis underwent tonsillectomy. Using size spectratyping and sequencing of TCR beta-chain variable region gene (TCRBV) rearrangements, we compared the TCR usage of psoriatic skin lesions, blood, tonsils, and tonsillar T cells fractionated according to the expression of the skin address in "cutaneous lymphocyte-associated Ag" (CLA). TCRBV-size spectratype analysis of the blood lymphocytes, tonsils, and the CLA-negative tonsillar T cells revealed largely unselected T cell populations. Instead, TCRBV gene families of the psoriatic lesions and skin-homing CLA-positive tonsillar T cells displayed highly restricted spectratypes. Sequencing of TCRBV cDNA identified various clonal TCRBV rearrangements within the psoriatic lesions that indicated Ag-driven T cell expansion. Several of these clonotypes were also detected within the tonsils and, in one of the patients, within the small subset of CLA-positive tonsillar T cells, suggesting that T cells from the same T cell clones were simultaneously present within skin and tonsillar tissue. Because after tonsillectomy psoriasis cleared in all three patients our observations indicate that T cells may connect psoriatic inflammation to streptococcal angina. They suggest that the chronic streptococcal immune stimulus within the tonsils could act as a source for pathogenic T cells in poststreptococcal disorders, and they may help to explain why eliminating this source with tonsillectomy may improve streptococcal-induced sequelae. 相似文献
87.
Ande SR Kommoju PR Draxl S Murkovic M Macheroux P Ghisla S Ferrando-May E 《Apoptosis : an international journal on programmed cell death》2006,11(8):1439-1451
L-amino acid oxidase (LAAO) from the Malayan pit viper induces both necrosis and apoptosis in Jurkat cells. Cell death by
necrosis is attributed to H2O2 produced by oxidation of α-amino acids. In the presence of catalase that effectively scavenges H2O2, a switch to apoptosis is observed. The major factors contributing to apoptosis are proposed to be: (i) generation of toxic
intermediates from fetal calf serum (ii) binding and internalization of LAAO. The latter process appears to be mediated by
the glycan moiety of the enzyme as desialylation reduces cytotoxicity. D-amino acid oxidase (DAAO), which catalyzes the same
reaction as LAAO but lacks glycosylation, triggers necrosis as a consequence of H2O2 production but not apoptosis in the presence of catalase. Thus induction of cell death by LAAO appears to involve both the
generation of H2O2 and the molecular interaction of the glycan moiety of the enzyme with structures at the cell surface.
S. R. Ande, P. R. Kommoju contributed equally to this work. 相似文献
88.
89.
Caspases are a family of cysteine proteases that are essential in the initiation and execution of apoptosis and the proteolytic maturation of inflammatory cytokines such as IL-1beta and IL-18. Caspases can be subdivided into those that have a large prodomain and those that have not. In general, apoptotic and inflammatory signalling pathways are initiated when large-prodomain caspases are recruited to large protein complexes via homotypic interactions involving death domain folds. The formation of these specialised multimeric platforms involves three major functions: (1) the sensing of cellular stress, damage, infection or inflammation; (2) multimerisation of the platform; and (3) recruitment and conformational activation of caspases. In this overview we discuss the complexes implicated in the regulation of cell death and inflammatory processes such as the death-inducing signalling complex (DISC), the apoptosome, the inflammasomes and the PIDDosome. We describe their sensing functions, compositions and functional outcomes. Inhibitory protein families such as FLIPs and CARD-only proteins prevent the recruitment of caspases in these sensing complexes, avoiding inappropriate initiation of cell death or inflammation. 相似文献
90.
Auweter SD Fasan R Reymond L Underwood JG Black DL Pitsch S Allain FH 《The EMBO journal》2006,25(1):163-173
The Fox-1 protein regulates alternative splicing of tissue-specific exons by binding to GCAUG elements. Here, we report the solution structure of the Fox-1 RNA binding domain (RBD) in complex with UGCAUGU. The last three nucleotides, UGU, are recognized in a canonical way by the four-stranded beta-sheet of the RBD. In contrast, the first four nucleotides, UGCA, are bound by two loops of the protein in an unprecedented manner. Nucleotides U1, G2, and C3 are wrapped around a single phenylalanine, while G2 and A4 form a base-pair. This novel RNA binding site is independent from the beta-sheet binding interface. Surface plasmon resonance analyses were used to quantify the energetic contributions of electrostatic and hydrogen bond interactions to complex formation and support our structural findings. These results demonstrate the unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, which is exceptional in its high affinity for a defined but short sequence element. 相似文献